Frances P. O’Malley

Tumor Characteristics Associated With Mammographic Detection of Breast Cancer in the Ontario Breast Screening Program

BACKGROUND Few studies have compared the prognostic value of tumor characteristics by type of breast cancer diagnosed in the interval between mammographic screenings with screen-detected breast cancers. METHODS We conducted a case-case study within the cohort of women (n = 431 480) in the Ontario Breast Screening Program who were aged 50 years and older and were screened between January 1, 1994, and December 31, 2002. Interval cancers, defined as breast cancers diagnosed within 24 months after a negative screening mammogram, were designated as true interval cancers (n = 288) or missed interval cancers (n = 87) if they were not identified at the time of screening but were identified in retrospect. Screen-detected breast cancers (n = 450) were selected to match interval cancers. Tumors were evaluated for stage, grade, mitotic index, histology, and expression of hormone receptors and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression. RESULTS Both true and missed interval cancers were of higher stage and grade than matched screen-detected breast cancers. However, true interval cancers had a higher mitotic index (OR = 3.13, 95% CI = 1.81 to 5.42), a higher percentage of nonductal histology (OR = 1.94, 95% CI = 1.05 to 3.59), and were more likely to be both estrogen receptor-negative (OR = 2.09, 95% CI = 1.32 to 3.30) and progesterone receptor-negative (OR = 2.49, 95% CI = 1.68 to 3.70) compared with matched screen-detected tumors. CONCLUSIONS In this study, interval cancers were of higher stage and grade compared with screen-detected cancers. True interval cancers were more likely to have additional adverse prognostic features of estrogen and progesterone receptor negativity and nonductal morphology. The findings suggest a need for more sensitive screening modalities to detect true interval breast cancers and different approaches for early detection of fast-growing tumors.

Papillary Lesions of the Breast: Impact of Breast Pathology Subspecialization on Core Biopsy and Excision Diagnoses

Background:Classifying papillary lesions of the breast on core biopsy (CB) is challenging. Although traditionally all such lesions were surgically excised, at present, conservative management of benign lesions is being advocated; therefore, accurately classifying papillary lesions on CB is all the more imperative. The extent to which subspecialty training in breast pathology might mitigate such difficulties in diagnosis has not yet been reported. We investigated change in diagnoses from CB to surgical excision according to subspecialist training in breast pathology and interobserver agreement between specialized breast pathologists (BPs) and nonbreast pathologists (NBPs) in classifying these lesions. Design:CBs of 281 papillary lesions from 266 patients diagnosed between 2000 and 2010 were classified by both a BP and NBP into benign, atypical, ductal carcinoma in situ/encapsulated papillary carcinoma, or invasive carcinoma categories. Rates of change in diagnostic category in the surgical excision specimen were calculated on the basis of: (i) the original diagnosis, (ii) diagnosis made by the BP, and (iii) diagnosis made by the NBP. Comparisons were made using the &khgr;2 test. Kappa values were calculated for interobserver agreement. Results:Of 162 lesions with subsequent excision, 90 were originally diagnosed as benign, 38 as atypical, 25 as ductal carcinoma in situ/encapsulated papillary carcinoma, and 9 as invasive on CB. The upgrade rate for benign papillomas to an atypical or malignant lesion on surgical excision was 22.2% according to the original diagnosis. This rate fell to 16.3% when the BP diagnoses were considered, compared with 26.3% for the NBP diagnoses. There was no significant difference between BPs and NBPs in the rate of upgrade from a benign to an atypical/malignant diagnosis, although downgrades from atypical/malignant to benign papillomas were more commonly seen among NBPs (P=0.002). Overall, the BP diagnosis on CB was less likely to differ from the excision diagnosis (P=0.0001). Benign papillomas upgraded on excision were more likely to occur with larger radiologic mass size (P=0.033) compared with those that were not upgraded. Of 8 benign papillomas upgraded to a malignant lesion on excision, 7 were discordant on radiology. Interobserver agreement between BP and NBP diagnoses was in the “fair agreement” range (&kgr;=0.38), with perfect agreement in 66.4% of cases. Conclusions:Correlation between CB and excision diagnoses for breast papillary lesions is significantly greater for BPs than for NBPs. This is largely because of a tendency to overcall atypia or malignancy on CB by NBPs. However, upgrades from benign to atypical or malignant did not significantly differ according to subspecialization. With accurate pathologic assessment and radiologic-pathologic correlation, the upgrade rate of benign papillomas to malignancy can be minimized significantly.

Clinical–pathologic significance of cancer stem cell marker expression in familial breast cancers

Human breast cancer cells with a CD44+/CD24−/low or ALDH1+ phenotype have been demonstrated to be enriched for cancer stem cells (CSCs) using in vitro and in vivo techniques. The aim of this study was to determine the association between CD44+/CD24−/low and ALDH1 expression with clinical–pathologic tumor characteristics, tumor molecular subtype, and survival in a well characterized collection of familial breast cancer cases. 364 familial breast cancers from the Ontario Familial Breast Cancer Registry (58 BRCA1-associated, 64 BRCA2-associated, and 242 familial non-BRCA1/2 cancers) were studied. Each tumor had a centralized pathology review performed. TMA sections of all tumors were analyzed for the expression of ER, PR, HER2, CK5, CK14, EGFR, CD44, CD24, and ALDH1. The Chi square test or Fisher’s exact test was used to analyze the marker associations with clinical–pathologic tumor variables, molecular subtype and genetic subtype. Analyses of the association of overall survival (OS) with marker status were conducted using Kaplan–Meier plots and log-rank tests. The CD44+/CD24−/low and ALDH1+ phenotypes were identified in 16% and 15% of the familial breast cancer cases, respectively, and associated with high-tumor grade, a high-mitotic count, and component features of the medullary type of breast cancer. CD44+/CD24−/low and ALDH1 expression in this series were further associated with the basal-like molecular subtype and the CD44+/CD24−/low phenotype was independently associated with BRCA1 mutational status. The currently accepted breast CSCs markers are present in a minority of familial breast cancers. Whereas the presence of these markers is correlated with several poor prognostic features and the basal-like subtype of breast cancer, they do not predict OS.

Clinical and prognostic factors associated with diagnostic wait times by breast cancer detection method

IntroductionAlthough prognostic differences between screen-detected, interval and symptomatic breast cancers are known, factors associated with wait times to diagnosis among these three groups have not been studied.MethodsOf the 16,373 invasive breast cancers diagnosed between January 1, 1995 and December 31, 2003 in a cohort of Ontario women aged 50 to 69, a random sample (N = 2,615) were selected for chart abstraction. Eligible women were classified according to detection method; screen-detected (n = 1181), interval (n = 319) or symptomatic (n = 406). Diagnostic wait time was calculated from the initial imaging or biopsy to breast cancer diagnosis. Logistic regression analysis examined associations between diagnostic wait times dichotomized as greater or less than the median and demographic, clinical and prognostic factors separately for each detection cohort.ResultsWomen who underwent an open biopsy had significantly longer than median wait times to diagnosis, compared to women who underwent a fine needle aspiration or core biopsy; (screen-detected OR = 2.76, 95% CI = 2.14-3.56; interval OR = 2.56, 95% CI = 1.50-4.35; symptomatic OR = 5.56, 95% CI = 3.33-9.30). Additionally, screen-detected breast cancers diagnosed with stage II and symptomatic cancers diagnosed at stage III or IV had significantly shorter diagnostic wait times compared to those diagnosed at stage 1 (OR = 0.66 95% CI = 0.50-0.87 and OR = 0.46, 95% CI = 0.25-0.85 respectively).ConclusionsOur study is consistent with expedited diagnostic work-up for breast cancers with more advanced prognostic features. Furthermore, women who had an open surgical biopsy had a greater than the median diagnostic wait time, irrespective of detection method.

Primary Basaloid Carcinoma of the Nipple with Associated Squamous Cell Carcinoma in Situ

Abstract:  Basaloid carcinomas have been documented in various anatomic locations. We describe a primary invasive adenocarcinoma of the nipple with extensive basaloid features that was also associated with squamous cell carcinoma (SCC) in situ and an aggressive behavior. A 69‐year‐old woman without a history of breast neoplasia presented with right nipple pain. Biopsy of the nipple revealed SCC in situ. One year later, she returned with nipple ulceration. An excisional specimen showed a 1.7 cm nodule composed of invasive sheets and ribbons of basaloid cells with numerous mitoses, extensive tumor necrosis and evidence of glandular differentiation. SCC in situ was present in the overlying epidermis. The differential diagnosis included a primary basaloid adenocarcinoma of the nipple, basal cell carcinoma of the nipple, neuroendocrine carcinoma, melanoma, basaloid variant of adenoid cystic carcinoma and metastatic disease. Immunohistochemical profile of this tumor supported a primary basaloid adenocarcinoma of the nipple. Although the initial sentinel lymph node biopsy was negative, within a year of diagnosis, the patient developed ipsilateral axillary node and pulmonary metastases. To the best of our knowledge, this is the first case of basaloid carcinoma to be documented in this anatomic site.